Journal of Applied Biotechnology & Bioengineering

Review Article Open Access Tumors associated with oncogenic and recombinant vaccines

Abstract Volume 5 Issue 3 - 2018 Oncogenic viruses are responsible by development of tumors as Human papillomavirus Dra Rachel Siqueira de Queiroz Simões, Dra (HPV) that infect the anogenital epithelium causing cervical cancer, anal and penis cancer. There are viral groups based on their oncogenic activity as high‒risk types, Ortrud Monika Barth low‒risk types and types of undetermined‒risk. Several biotechnological assays are Laboratory of Morphology and Viral Morphogenesis, Instituto based on the production of recombinant products originated by the interaction of Oswaldo Cruz, Brazil a viral genome with the genome of a host cell as bacteria, yeast, cell cultures and Correspondence: Dra Rachel Siqueira de Queiroz Simões, insects. Recently have been used ‒like particles (VLP) independently of the viral Laboratory of Morphology and Viral Morphogenesis, Instituto genome since some viral particles have the ability to self‒assembling. There are some Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil 4365, approved VLP vaccines as HPV vaccines, Hepatitis B and E vaccines and other VLP 21040‒900, Rio de Janeiro, Brazil, based vaccines under development such as using Human B19 parvovirus‒like particles, Email [email protected] Influenza vaccine candidates, Norwalk virus, Ebola and Marbug virus, Hepatitis C, Human immunodeficiency virus (HIV) as vaccine candidates. The aim of this present Received: April 20, 2018 | Published: May 16, 2018 study was to address some examples of virus causing tumors and their respective recombinant protein based virus‒like particle vaccines. Besides of HPV, also will also be addressed Hepatitis C virus (HCV), Hepatitis (HBV), Herpesvirus (HSV), Virus (HSV‒1) and (HSV‒2), Human Herpesvirus 3 (HHV‒3), Human Herpesvirus 4 (HHV‒4) or Epstain‒Barr virus (EBV), Human Herpesvirus‒5 (HHV‒5) or Human (HCMV), (HHV‒6), Human Herpesvirus 7 (HHV‒7) and Human Herpesvirus 8 (HHV‒8), also known as Kaposi’s sarcoma‒associated herpesvirus (KSHV). There are several challenges in the production of the virus‒like particles based recombinant vaccines under development using specific cell lines and assays with laboratory animals. It is important to reflect about on the extent to which the pharmaceutical industries are willing to develop recombinant vaccines in the prevention of tumor associated diseases.

Keywords: diseases, oncogenic viruses, recombinant vaccines, tumors

Abbreviations: HPV, human papillomavirus; VLP, virus‒ are other VLP based vaccines under development such as using like particles; HIV, human immunodeficiency virus; HCV, hepatitis Human B19 parvovirus‒like particles,2 Influenza vaccine candidates, C virus; HSV, herpesvirus; HSV‒1, herpes simplex virus; HSV‒2, Norwalk virus, Ebola and Marbug virus, Hepatitis C, Human herpes simplex virus; HHV‒3, human herpesvirus 3; HHV‒4, immunodeficiency virus (HIV) as vaccine candidates.1 However, the human herpesvirus 4; EBV, epstain‒barr virus; HHV‒5, human focus of the present scientific considerations address some examples herpesvirus‒5; HCMV, human cytomegalovirus; HHV‒6, human of virus causing tumors and their respective recombinant protein herpesvirus 6; HHV‒7, human herpesvirus 7; HHV‒8, human based virus‒like particle vaccines. herpesvirus 8; KSHV, kaposi’s sarcoma‒associated herpesvirus; Human papillomavirus (HPV) MCD, multicentric castleman’s disease Papillomaviruses are non‒enveloped viruses presenting a Introduction closed circular double‒stranded non‒segmented DNA genome Several viruses are causing tumors and are called oncogenic of approximately 8 kb. HPV induce the most common sexually transmitted disease and has been classified in theAlphapapillomavirus viruses. Once introduced into an organism, the strategies taken are 3,4 virus‒specific, reaching organs predestined to the development of genus. Detection of viral DNA sequences of the L1 gene, the tumors. Vaccines, of variable efficacy have been developed over the stable and most conserved region of the viral genome, has been years, making use of the most diverse biotechnological production. generally performed. More than 200 HPV genotypes and several The most recent are based on the production of recombinant products HPV types associated with particular diseases as oral lesions originated by the interaction of a viral genome with the genome of (Hecks disease, oropharyngeal , laryngeal papillomas), a host cell (bacteria, yeast, cell cultures, insects, etc.), which will anogenital (Bowenoid papulosis, Buschike‒Lowenstein express the desired proteins for immunization in case of infection tumor), Epidermodysplasia verruciformis (plane warts, Pityriasis‒ like plaques, squamous cell of sun‒exposed skin) have by an infectious viral agent. Some viral particles have the ability to 5,6 self‒assemble into virus‒like particles (VLP) independently of the been described. HPV vaccination is the best preventive strategy viral genome. There are some approved VLP vaccines as Human against cervical cancer, cervical intraepithelial neoplasia and genital papillomavirus (HPV) vaccines, Hepatitis B and E vaccines.1 There warts. A recombinant DNA technology has allowed the development

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of prophylactic vaccines for HPV. Licensed HPV recombinant New biotechnologies in molecular biology as quimeric vaccine vaccines, as bivalent (Cervarix®) against HPV16/18, quadrivalent production using conserved peptides are possible candidates of (Gardasil®) target HPV16/18/6/11 and nonavalent (Gardasil‒9®) peptide vaccine against HCV infection.10 Some studies involved target HPV16/18/31/33/45/52/58/6/11 have been applied in many the detection of antibodies in rabbits with immunogenic potentially countries.4,5 Baculovirus and yeast (Saccharomyces cerevisiae) were activity by synthetic peptides of the HCV envelope glycoprotein E2 the target as an expression system. Papillomaviruses can be used as in chronic HCV infections.11 Until the date HCV vaccine has not been viral vectors in the gene therapy and new therapeutic targets have available. been successfully applied by recombinant DNA methods.1,5 Hepatitis B virus (HBV) The Human papillomavirus (HPV) is critical in the pathogenesis of cervical cancer, the most common cancer among women. The Hepatitis B virus (HBV) is classified in the Hepadnaviridae natural history and epidemiologic studies of HPV are key tools for family. This family is divided into two genera: Orthohepadnavirus possible changes in cervical screening and vaccine immunization and Avihepadnavirus. The genome is composed of a 3,200base pairs strategies. Several studies discuss the molecular detection of viral (bp) of a circular double stranded DNA presenting four open reading DNA sequences in recombinant DNA products and the interaction of frames (ORFs) designated as: Pre‒S/S, Pre C/C, P and X. The Pre‒S/S viral chromatin with the host cell chromatin during viral replication. corresponds to the Hepatitis virus surface gene (HBsAg). The One of the research approaches investigates morphological Pre‒S1, Pre‒S2 and S regions have three initiation codons in the same alterations of HPV‒positive human cervical carcinoma cell lines reading phase that, after being translated, originate the proteins: L (SiHa and HeLa) as possible prognostic markers of cervical cancer. “Large” (400aa), Middle “M” (281aa) and “Small” (226aa). These Gene therapy has a great potential as a new therapeutical modality three proteins that comprise the HBsAg are found in the serum of in keratinocyte reprogramming, which can be a crucial point for the infected individuals in two ways: Small glycosylated (GP27) and study of HPV tumors associated in regenerative medicine at the tissue Small non‒glycosylated (P24), Middle glycosylated (GP33) and engineering laboratories. New biotechnologies in molecular biology Middle di-glycosylated (GP36), and Large glycosylated (GP42) and 14 have been applied in research of HPV and are being investigated in Large non‒glycosylated L (P39). 1,4,6 gene therapy. HBV is one of the major causative agents of chronic liver disease. Hepatitis C virus (HCV) It is estimated that about 350million people worldwide are carriers of the HBV and approximately 2 million are infected individuals in Hepatitis C virus (HCV) belongs to the Nidovirales order, Brazil. The first reports of variability of the Hepatitis B virus (HBV) Flaviridae family, Hepacivirus genus. HCV is an enveloped virus were described by Le Bouvier (1971), who identified two mutually presenting a single strand of positive polarized RNA genome with exclusive antigenic determinants, d and y, located in HBsAg. Two approximately 9,400 nucleotides. HCV illness is a chronic infection additional determinants, w and r, were subsequently enunciated by that affects more than 2% of the global population and causes end‒ Bancroft et al. (1972).14 Thus, nine subtypes have been described: stage liver diseases as chronic hepatitis. It is a worldwide public ayw1, ayw2, ayw3, ayw4, adw2, adw4, ayr, adrq+ and adrq‒, which health problem that affects more than 70% of the estimated 170 share a common conformational epitope present in HBsAg. There are million people inducing chronic lesions hepatitis. This virus leads eight HBV genotypes (identified as A‒H) that exhibit more than 8% to severe fibrosis and cirrhosis, hepatic failure, or hepatocellular divergence between complete genomic sequences. The analysis of carcinoma. HCV has a higher rate of mutation existing inside an genomic variability of HBV isolates is fundamental for molecular and individual as quasispecies.7 HCV is divided into six genotypes and epidemiological studies.14,15 multiple subtypes.8 The envelope glycoproteins E1 and E2 are the HBV infection produces two types of viral particles: full, spherical, natural targets to neutralizing antibodies response, but are also the two HBV genome‒containing infectious particles (42nm), as well as of the most variable HCV proteins. Production of specific antibodies non‒infectious spherical or filamentous (22nm) subviral particles in rabbits against conserved and potentially immunogenic peptides of composed exclusively of HBsAg. An expression system (as used in the HCV envelope glycoprotein E2 has been described. the Papilloma vaccines, the first recombinant vaccine licensed and HCV displays a high variability and is classified into seven produced from yeast expression) was used for Hepatitis B surface‒ genetically distinct genotypes which differ by approximately 30% at antigen isolation from human plasma of chronic HBV patients the nucleotide level. Envelope (E1/E2) proteins of HCV may generate (Heptavax‒B, Merck & Co), and was released in 1981.16 neutralizing antibodies. At the end N‒terminus of the E2 protein there Worldwide over the last 30years, HBsAg has been used as a is a region of 27 amino acids called hypervariable region 1 (HVR1), commercial vaccine against hepatitis B. Actually, there are two types very important in neutralizing HCV. Despite the high degree of of successful vaccines based on virus‒like particles (VLP) involving variability of E2 protein, some amino acid positions are conserved Hepatitis B virus surface antigen (HBsAg) and core antigen (HBcAg) and this protein is the target of several neutralizing monoclonal expressed in Escherichia coli.1,17 Conditions on the immunogenicity antibodies.8‒11 More biotechnological studies are need to investigate can be tested in mice with alternative routes of administration of HBV the clinical and epidemiological aspects and to associate the presence vaccine and novel formulations assays.1 of antibodies with the progression of liver diseases.1,12 However, the high variability of this antigenic fragment plays a key role in the viral The development of recombinant vaccines composed exclusively escape mechanism of the host immune response and represents the of HBsAg (Engerix‒B, SmithKline and Recombivax, Merck & major obstacle in the development of an HCV vaccine.13 Co) was possible with the advance of genetic engineering. New

Citation: Simões RSQ, Barth OM. Tumors associated with oncogenic viruses and recombinant vaccines. J Appl Biotechnol Bioeng. 2018;5(3):151‒154. DOI: 10.15406/jabb.2018.05.00131 Copyright: Tumors associated with oncogenic viruses and recombinant vaccines ©2018 Simões et al. 153

researches have investigated the improvement of the vaccine model (HCMV) belong to the family, Betaherpesviridae of heterological antigens based on hepatitis B virus envelope protein subfamily, Cytomegalovirus genus. They are frequently detected in containing HCV antigen as a quimeric vaccine. transplanted patients and immunocompetent individuals, where they mediate early (IE) proteins that are responsible for the regulation of the Herpesvirus (HSV) early (E) proteins involved in cell regulation including the expression Another oncogenic virus is the Herpesvirus (HSV) which viral and transport of the HLA antigens (class I MHC proteins) to the replication sites occur inside the cell nucleus. HSV can infect and proteasome. In particular, the phosphoprotein pp65 can be used as 22 establish latent infections as in mice, guinea pigs, rabbits and humans. early markers of the virus infection in cell cultures. The reactivation The viral genome in a latent state (episomal) has been described inside in transplantation patients has been performed by quantitative HCMV the nucleus of sensory ganglions. DNA detection from whole blood or plasma and quantitative detection of pp65 antigen in neutrophil granulocytes.22 Antiviral agents, that Herpes simplex virus (HSV‒1) and herpes simplex are currently available, are used for prevention and therapeutics of virus (HSV‒2) HCMV. Clinical assays for the development of vaccines don´t have been successful due to the latent infection cycle of the virus and are Herpes simplex virus (HSV‒1) or Human herpesvirus 1 (HHV‒1) not yet available. 22 induce an acute infection accompanied by the formation of labial vesicles in the oral region. Herpes simplex virus (HSV‒2) or Human Human herpesvirus 6 (HHV‒6) and human herpesvirus herpesvirus 2 (HHV‒2) are causing strong lesions in the genital 7 (HHV‒7) area. These herpesviruses are members of the Alphaherpesviruses subfamily. There are no licensed vaccines against HSV‒1 and Human herpesvirus 6 (HHV‒6) induces severe cutaneous eruptions HSV‒2,18 despite there are preventive and therapeutic vaccines and . Human herpesvirus 7 (HHV‒7) has been detected in 23 for HSV‒2, specially of various stages of development in clinical patients with pityriasisrosea, a common papulosquamous disease. testing.19 Both viruses are closely related β‒herperviruses and classified in the Herpesviridae family, subfamily, Human herpesvirus 3 (HHV‒3) genus. The genome of HHV‒6 is of a linear double‒stranded DNA with 159 to 170kbp containing approximately 100 genes, while the Human herpesvirus 3 (HHV‒3) or varicella‒zoster virus is highly HHV‒7 genome has only 133kbp.The primary infection cause subit contagious and has approximately 69 different genes being five exanthema. The viruses are secreted by saliva in healthy populations homologous genes of HSV. It is classified in the and viral reactivation occurs in immuno‒compromised individuals subfamily and the Varicellovirus genus with DNA of 125kbp, which is (AIDs patients stressed and transplanted patients). HHV‒6 was lower than the HSV (152kbp). Primary varicella‒zoster virus infection isolated from the peripheral blood lymphocytes of patients with causes varicella () and when occurs the reactivation of latent lymphoproliferative disorders and it was initially found within B cells virus, usually causes herpes zoster in adults manifesting as vesicular of infected individuals. Posteriorly, CD4+ T cells were the major cell rash. The Advisory Committee on Immunization Practices and Center type infected by HHV‒6. In 1991, researchers discovered two variants for Diseases Control and Prevention (CDC) recommends for Herpes of HHV‒6 designed HHV‒6A and HHV‒6B with 90% of genetic Zoster prevention a single dose of Zostavax® (live attenuated virus similarity. Both variants of HHV‒6 A, B and HHV‒7 presenting with vaccine) for people 60 years old or older. This vaccine is not indicated 20%‒75% nucleic acid homology depending on the genes.23 There are for the treatment of zoster or (PHN) and is not no commercially available recombinant vaccines for the treatment of indicated for prevention of primary varicella infection (Chickenpox).20 HHV‒6 and 7, only therapeutic measures with the administration of Human herpesvirus 4 (HHV‒4) antiviral agents as for example in patients who have undergone bone marrow transplantation. However, mutations in homologous genes Human Herpesvirus 4 (HHV‒4) or Epstain‒Barr virus (EBV), a such as the HHV‒6 U69 gene that is homologous to the HCMV UL97 member of the Gammaherpesvirus subfamily, was discovered in 1964 gene is associated with decreased efficacy of ganciclovir. by Tony Epstein and Yvone Barr in tumor cells of patients presenting Burkitt’s lymphoma. There are three latency forms: Lat I, LatII and Human herpesvirus 8 (HHV‒8) Lat III. The Lat I site express the single protein EBNA 1 (Epstein‒ The Human Herpesvirus 8 (HHV‒8), also known as Kaposi’s Barr nuclear antigen) and express two sites of RNA (Epstein‒Barr sarcoma‒associated herpesvirus (KSHV), is classified in the order early RNA‒EBERS) and (Bam A). The Lat II site express additional Herspesvirales, Herpesviridae family, proteins (latent membrane protein ‒ LMPs) and Lat III express more subfamily and Rhadinovirus genus. The DNA viral genome is proteins as EBNAs 2, 3A, 3B, 3C and LP. There are several types of composed of a 145 kbp region containing all open reading frame tumors associated with Epstein‒Barr virus (EBV) such as Burkitt’s sequences. There are HHV8‒exclusive ORFs designated K (ORF lymphoma, Hodgkin’s disease, T‒Cell lymphoma, post‒transplant K1‒K15) being possible by sequencing hypervariable regions of the lymphoproliferative disease, nasopharyngeal carcinoma, gastric viral genome, such as ORF‒K1 to identify 5 viral subtypes (A‒E). carcinoma and Leiomyosarcoma.21 EBV peptide vaccine has been HHV‒8 is associated with Kaposi’s Sarcoma (KS) of HIV positive tested in the rabbit model using immunogenic epitopes selected to and negative patients, and of two rare lymphoproliferative disorders: stimulate both the T as well as B lymphocytes.18 the Primary Effusion Lymphomas (PELs), called also Body‒cavity‒ Human herpesvirus‒5 (HHV‒5) based lymphoma (it is a B cells lymphoma not the Hodgkin tumor), and the Multicentric Castleman’s disease (MCD). DNA vaccines are Human Herpesvirus‒5 (HHV‒5) or Human Cytomegalovirus of circular double‒stranded plasmid DNA (pDNA) molecules and

Citation: Simões RSQ, Barth OM. Tumors associated with oncogenic viruses and recombinant vaccines. J Appl Biotechnol Bioeng. 2018;5(3):151‒154. DOI: 10.15406/jabb.2018.05.00131 Copyright: Tumors associated with oncogenic viruses and recombinant vaccines ©2018 Simões et al. 154

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Citation: Simões RSQ, Barth OM. Tumors associated with oncogenic viruses and recombinant vaccines. J Appl Biotechnol Bioeng. 2018;5(3):151‒154. DOI: 10.15406/jabb.2018.05.00131